Squamous cell carcinoma of the head and neck is diagnosed in over 40,000 Americans each year, resulting in over 12,000 annual deaths (Parker et al, CA Cancer J. Clin. 46: 5-27 (1996)). Carcinomas of the head and neck are often associated with multiple areas of dysplasia or carcinoma in situ (CIS) in noncontiguous mucosa, as well as with the development of second primary cancers of the aerodigestive tract. This concept of "field cancerization" was introduced by Slaughter in 1953, hypothesizing that the epithelium becomes "preconditioned" from exposure to carcinogenic agents, thus priming it for subsequent development of invasive lesions after additional genetic hits occur (Slaughter et al, Cancer. 6: 963-968 (1953)).
Modern molecular biological techniques have supported and greatly expanded the knowledge of the "cancer field effect". Specifically, it has been demonstrated by analysis of X-chromosome inactivation in female patients with multiple head and neck cancers that distinct tumors may arise from the regional clonal growth of phenotypically normal, mutated preneoplastic cells (Bedi et al, Cancer Res. 56: 2484-2487(1996)). Chromosomal studies evaluating for loss of heterozygosity (LOH) in hyperplastic, dysplastic, CIS, and invasive lesions have identified that LOH at loci on 9p21-22 (corresponding to the cyclin-dependent kinase inhibitor, p16, as well as other possible tumor suppressor genes) and 3p (with three possible tumor suppressor genes) occurs early in tumor promotion (Waber et al, Oncogene. 15: 1699-704 (1997), Califano et al, Cancer Res. 56: 2488-2492 (1996)). Inactivation of p53 through LOH and subsequent mutation of the remaining allele has also been shown to occur in the progression from preinvasive to invasive carcinoma (Califano et al, Cancer Res. 56: 2488-2492 (1996)). Allelic loss at 4q26-28, 6p, 8p, 8q, 11q13, 13q, 14q31-32.1 and more recently 2q has also been observed in head and neck cancer (Bedi et al, Cancer Res. 56: 2484-2487(1996), Waber et al, Oncogene. 15: 1699-704 (1997), Califano et al, Cancer Res. 56: 2488-2492 (1996), Nawroz et al, Cancer Res. 54: 1152-5 (1994), Yoo et al, Cancer Res. 54: 4603-6 (1994), Ransom et al, Head Neck. 20: 404-10 (1998), Lydiatt et al, Head Neck. 20: 113-8 (1998), Callender et al, Cancer. 74: 152-8 (1994)).
The mannose-6-phosphate/insulin-like growth factor 2 receptor (M6P/IGF-II receptor) is a tumor suppressor located on 6q26 that has been shown to be inactivated in breast, liver and lung cancer (De Souza et al, Oncogene. 10: 1725-9 (1995), De Souza et al, Nat. Genet. 11: 447-9 (1995), Yamada et al, Proc. Natl. Acad. Sci. USA. 94: 10351-5 (1997), Hankins et al, Oncogene. 12: 2003-9 (1996)). This receptor regulates cell growth by binding and inactivating the mitogen, IGF2, and activating the growth inhibitor, transforming growth factor beta (TGF.beta.) (De Bleser et al, Hepatology. 21: 1429-37 (1995), Dennis et al, Proc. Natl. Acad. Sci. USA. 88: 580-4 (1991), Kornfeld et al, Annu. Rev. Biochem. 61: 307-330 (1992)). The M6P/IGF-II receptor has also been shown to be mutated in gastrointestinal and endometrial malignancies with mismatch repair enzyme deficiencies and microsatellite instability (Souza et al, Nat. Genet. 14: 255-257 (1996), Ouyang et al, Cancer Res. 57: 1851-1854 (1997)). Furthermore, chronic hepatitis virus infection of the liver results in the inactivation of a single allele of the M6P/IGF-II receptor, and the clonal expansion of normal appearing, M6P/IGF-II receptor-mutated preneoplastic hepatocytes from which the majority of HCCs ultimately develop (Yamada et al, Proc. Natl. Acad. Sci. USA. 94: 10351-5 (1997)). Thus, M6P/IGF-II receptor inactivation occurs frequently and early in liver carcinogenesis.
The present invention results from the demonstration that LOH occurs at the M6P/IGF-II receptor locus in over 50% of head and neck cancers and that this LOH is predictive of a poor therapeutic outcome.